Many new antiviral drugs, mainly nucleoside analogues, have been introduced over the past 20 years for therapy of herpes simplex virus (HSV) infections. Although some antivirals are effective in experimental animal models, only a few are useful in the therapy of human herpes keratitis or encephalitis and none have proven effective in the therapy of HSV-1 or HSV-2 mucocutaneous lesions. The lack of efficacy was demonstrated by recent randomized, placebo-controlled, blinded studies of topical therapy of HSV-1 infections in theorofacial area. Since penetration of skin is not assured by topical therapy, failure may have been due to lack of penetration. We propose to use iontophoresis to assure penetration in our clinical trials of antiviral therapy. Iontophoresis is a method of choice for delivery of ionic drugs to surface tissues. Recently we demonstrated in mice that 1) iontophoresis of adenine arabinoside monosphate (Ara-AMP) provides an antiviral concentration in skin for at least 24 hours; 2) Ara-AMP provides an antiviral concentration in skin for at least 24 hours; 2) Ara-AMP is metabolized primarily to the active antiviral Ara-A; and 3) Ara-AMP or ACG iontophoresis to HSV-1 or HSV-2 skin lesions arrests infection, preventing encephalitis, and death. Also, preliminary, open clinical trials in six human subjects (14 lesions) using idoxuridine iontophoresis for recurrent orofacial herpes labialis (RHL), indicated immediate relief of symptoms, rapid healing and fewer, less severe recurrences. Achieving similar therapeutic results with either Ara-AMP or acyclovir (ACG) iontophoresis is our long term objective. Our specific aims are to compare therapy of RHL by either Ara-AMP or ACG iontophoresis to placebo, using controlled, blinded clinical trials. Photographic, viral and symptomatic evidence of effectiveness will be obtained using randomized comparisons and Bross' sequential analysis design. Other specific aims include the study of the efficacy of iontophoresis in: 1) reduction of recurrence frequency and severity and 2) usefulness for therapy of non-orofacial cutaneous lesions. Experimental evidence available strongly supports conducting the proposed clinical trials of Ara-AMP and ACG applied by iontophoresis. Such studies will allow assessment of this most promising therapy for cutaneous HSV infections and provide a rationale for study of use in genital and ocular HSV infections.